1. Field of the Invention
The present invention relates to a method for enhancing the bioavailability of nutritional compounds. The present invention also relates to compositions for such enhancement.
The fifty percent increase in life expectancy of Americans from 1930 to 1980 can, in part, be attributed to the improvement in nutrition in the United States during that period. However, the situation today remains far from ideal, since six out of ten of the leading causes of death in this county, including heart attack, cancer, cirrhosis of the liver, and diabetes, are linked to diet. It becomes increasingly obvious that many of those diseases could be prevented with a well balanced diet and efficient nutritional supplementation with certain vitamins and minerals.
The problem is particularly severe in older Americans. Approximately 30 percent of older Americans do not get the dietary requirements of all the essential nutrients. The hazards of food-drug interactions in depleting essential nutrients are well recognized. It is unavoidable that old age calls for increased use of medications. For example, use of certain antibiotics decreases absorption of calcium and iron, while EDTA chelation therapy decreases absorption of zinc, iron, copper, and magnesium.
In addition, many foods which increase the risk of cancer and cardiovascular disease have to be eliminated from the diet, which further depletes the sources of essential nutrients. For example, excellent sources of vitamin B and vitamin D, such as red meat, liver, egg yolk, cheese and dairy products, are often limited because of their high cholesterol content.
Limited menu also causes a depletion of essential amino acids, such as tryptophan, which is important precursor of neurotransmitters, and may play a role in the prevention of brain deterioration with aging.
The availability of essential nutrients is further compromised by poor gastrointestinal absorption.
The traditional way to offset insufficient nutrient supplementation, insufficient gastrointestinal absorption and insufficient metabolic utilization of essential nutrients is to administer large doses of compensating materials, such as vitamin and mineral supplements.
The present invention provides an alternative method for improving nutritional status by increasing the bioavailability of various nutritional materials.
The bioavailability of nutrients is also relevant to animal health as well as human health. Thus, the compositions and methods of the invention are also intended to be used in veterinary practice.
2. Description of Related Art
Documents describing ayurvedic medicine dating from the period between the seventh century B.C. and the sixth century A.D. describe "trikatu". Trikatu is a Sanskrit word meaning three acrids, and refers to a combination of black pepper (Piper nigrum Linn.), long pepper (Piper longum Linn.) and ginger (Zingiber officinale Rosc.). In traditional ayurvedic medicine these drugs are essential ingredients of many prescriptions and formulations used for a wide range of diseases. Experimental evidence shows that the use of "trikatu", and its constituents individually as well as collectively, enhances the bioavailability of a number of drugs. In those studies carried out in animals as well as human volunteers, it was noted that the active component responsible for the increase in bioavailability of various drugs was piperine.
Piperine, or mixtures containing piperine, have been shown to increase the bioavailability, blood levels and efficacy of a number of drugs including ingredients of vasaka leaves (Bose, K. G., (1928) Pharmacopeia India, Bose Laboratories, Calcutta), vasicine (Atal et al., Journal of Ethnopharmacology, 4, 229-233 (1981)), sparteine (Atal et al., ibid), sulfadiazine (Atal et al., ibid), rifampicin (Zutshi, U. et al. (1984) Journal of the Association of Physicians of India, 33, 223-224), phenytoin (Bano et al., Planta Medica, 1987, pp. 568-569), pentobarbitone (Majumdar, A. N. et al. (1990), Indian Journal of Experimental Biology, 28, 486-487), theophylline (Bano et al., Eur. J. Clin. Pharmacol. (1991) 41:615-617) and propranolol (ibid).
The effect of piperine on the bioavailability of propranolol has been studied. The chronic oral administration of the anti-hypertensive agent propranolol is frequently rendered difficult due to the fact that steady therapeutic levels of this drug are not achieved or maintained. In addition, large doses are needed to be administered for efficacy and this frequently causes side-effects. Piperine has been shown to enhance the bioavailability of this drug. Propranolol administered with piperine shows a significant increase in plasma levels of the drug, presumably due to decrease in metabolism by the liver.
Similar results have been obtained with piperine and vasicine, theophylline, and phenytoin. Piperine has also been added in multi-drug formulations for the treatment of tuberculosis and leprosy. A formulation containing rifampicin, pyrazinamide and isoniazid has been tested in human volunteers (Indian Patent No. 1232/DEL/89). For most drugs, the comparative levels and peak concentration of the drugs in the presence of piperine were higher. The applicability of these results to the development of anti-tuberculosis and anti-leprosy formulations, which are presently cost prohibitive in developing countries, is apparent. Bioavailability enhancement helps to lower dosage levels and shorten the treatment course.
In summary, all of these examples clearly illustrate the role of piperine as a drug bioavailability enhancer. The combination of piperine with tested drugs is effective primarily due to higher plasma concentration and a longer stay of the drugs in the body. The reduced dose of highly toxic drugs and their enhanced efficacy is obviously desirable.
The effective bioenhancing dose of piperine for drug compounds varies, but the prior art studies indicate that a dose of approximately 10% (wt/wt) of the active drug could be regarded as an appropriate bioenhancing dose for most drugs.
There are two plausible explanations of the role that piperine may have in drug bioavailability: a) non-specific mechanisms promoting rapid absorption of drugs and nutrients, e.g., increased blood supply to the gastrointestinal tract, decreased hydrochloric acid secretion which prevents breakdown of some drugs, increased emulsifying content of the gut, increased enzymes like gamma-glutamyl transpeptidase which participate in active and passive transport of nutrients to the intestinal cells, and b) non-specific mechanisms inhibiting enzymes participating in biotransformation of drugs, preventing their inactivation and elimination. See: Annamalai, A. R., Manavalan, R. (1990) Effects of `Trikatu` and its individual components and piperine on gastrointestinal tracts: Trikatu--a bioavailable enhancer. Ind. Drugs 27(12); pp. 595-604; Johri, R. K. et al. (1992) Piperine-mediated changes in the permeability of rat intestinal epithelial cells. Bioch. Pharmacol. 43; pp. 1401-1407; Atal, C. K. et al. (1985) Biochemical basis of enhanced drug availability by piperine: Evidence that piperine is a potent inhibitor of drug metabolism. J. Pharmacol. Exp. Therap. 232; pp. 258-262; and Singh, J. et al. (1986) Piperine-mediated inhibition of glucuronidation activity in intestine: evidence that piperine lowers the endogenous UDP-glucuronic acid content. J. Pharmacol. Exp. Therap. 2236; pp.448-493.
Most drugs co-administered with piperine are probably more bioavailable as a result of both of the mechanisms, i.e., increased absorption from the gut and the slow down of biotransformation, inactivation and elimination from the system. The latter mechanism is probably the most important in sustaining the elevated blood levels of the drug, and making it more bioavailable to the tissue. Although a rapid absorption to the blood stream may account for increased blood levels of the drug, it is the inhibition of drug biotransforming enzymes with piperine that makes a drug stay in the body longer, in higher quantities, which makes it more effective.
Based on available literature data, it seems that piperine in a daily dose of at least 20 mg per person operates through inhibiting enzymes that would otherwise biotransform and speed up elimination of many drugs (Zutshi, U. et al. (1989) A process for the preparation of pharmaceutical combination with enhanced activity for treatment of tuberculosis and leprosy. Indian Patent No. 1231/Del/89; Zutshi et al. (1984) Influence of piperine on rifampicin blood levels in patients of pulmonary tuberculosis. J. Assoc. Phys. Ind. 33; pp. 223-224; Ban, C. K. et al. (1991) The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. European J. Clin. Pharm. 41; pp. 615-618 and Bano, G. et al. (1978) The effect of piperine on the pharmacokinetics of phenytoin in healthy volunteers. Planta Medica 53; pp. 568-570).
Interestingly, the dose of piperine that inhibits the biotransforming enzymes operates regardless of whether it is administered concurrently with the drug. This point can be illustrated by experiments with theophylline and phenytoin, where 20 mg of piperine was administered for seven days prior to the administration of either drug [Ban, C. K. et al. (1991) The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. European J. Clin. Pharm. 41; pp. 615-618 and Bano, G. et al. (1978) The effect of piperine on the pharmacokinetics of phenytoin in healthy volunteers. Planta Medica 53; pp. 568-570]. Since that regimen resulted in increased blood levels of the administered drugs, and dramatically prolonged the elimination time, the plausible explanation is that the prior administration of piperine inhibited drug biotransforming enzymes. In fact, this seems to be the only explanation for the increased bioavailability, since piperine administered separately from the drug could not possibly affect gastrointestinal events leading to its rapid absorption.
Another interesting observation is that doses of piperine below what is considered effective in inhibiting the biotransforming enzymes, may still be sufficient to enhance the rapid absorption of a drug from the gut. This phenomenon can be illustrated by the co-administration of piperine with the anti-hypertensive drug propranolol (Zutshi, U. et al. (1989) A process for the preparation of pharmaceutical combination with enhanced activity for treatment of tuberculosis and leprosy. Indian Patent No. 1231/Del/89).
Propranolol when administered with piperine showed a significant increase in blood levels. The maximum blood concentration of the drug increased two fold with piperine. Importantly, despite dramatically improving the bioavailability of propranolol, piperine, as used in a 3 mg dose, did not affect the elimination rate of the drug.
In an experimental design distinct from previous studies, the anti-asthmatic drug theophylline and the anti-epileptic drug phenytoin were tested (Ban, C. K. et al. (1991) The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. European J. Clin. Pharm. 41; pp. 615-618 and Bano, G. et al. (1978) The effect of piperine on the pharmacokinetics of phenytoin in healthy volunteers. Planta Medica 53; pp. 568-570). The study was done on six healthy volunteers. The participants were pretreated with 20 mg of piperine daily for seven days before receiving 150 mg of theophylline or 300 mg of phenytoin.
The maximum concentration of theophylline was 1.5 times higher in subjects pretreated with piperine. Importantly, the elimination rate of the drug was significantly slowed down with piperine pretreatment.
Phenytoin blood concentration rose more rapidly in the group pretreated with piperine than in the group receiving the drug alone. The pretreated group attained maximum concentration of the drug in shorter time and in significantly higher concentrations. The pretreatment with piperine resulted in significantly slower elimination of the drug.
The prior art discussed above clearly illustrates the role of piperine as a bioavailability enhancer, and the importance of its effective dose on the overall mechanism of enhanced bioavailability.
In the case of propranolol, the co-administration with only 3 mg of piperine resulted in doubling its blood levels, but without slowing down the drug elimination rate. Thus, it may be inferred that, in a small dose, piperine may not inhibit the biotransforming enzymes or affect the elimination rate of a drug. Rather, it may operate through enhancement of gastrointestinal events leading to rapid absorption mechanisms.